Method of preparing amine stereoisomers

ABSTRACT

This invention provides a method of preparing amine stereoisomers, which comprises stereoselectively reducing a sulfinylimine that bears on the sulfinyl group a residue of an alcohol, thiol or amine, or reacting a sulfinylimine stereoisomer that bears on the sulfinyl group a residue of an alcohol, thiol or amine with a source of a nucleophile, to afford a sulfinylamine stereoisomer, followed by contacting the sulfinylamine stereoisomer with a reagent suitable for the cleavage of a sulfur-nitrogen bond, to afford an amine stereoisomer. It also provides novel intermediates useful in the method, and the use of certain of the intermediates in the preparation of sulfoxide and sulfinylamine stereoisomers.

This invention relates to a method of preparing amine stereoisomers, tonovel intermediates useful in the method and to use of certain of thenovel intermediates in a method of preparing sulfoxide and sulfinylaminestereoisomers.

Many amine stereoisomers possess useful biological properties. Forexample, sibutramine is a neuronal monoamine reuptake inhibitor, whichhas the chemical name[N-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl]-N,N-dimethylamine.Originally disclosed in U.S. Pat. Nos. 4,746,680 and 4,806,570,sibutramine inhibits the reuptake of norepinephrine and, to a lesserextent, serotonin and dopamine. See, e.g., Buckett et al., Prog.Neuro-psychopharn. & Biol. Psychiat., 12:575-584, 1988; King et al., J.Clin. Pharm., 26:607-611 (1989).

Racemic sibutramine is sold as a hydrochloride monohydrate under thetradename MERIDIA®, and is indicated for the treatment of obesity.Physician's Desk Reference®1509-1513 (54^(th) ed., 2000). The treatmentof obesity using racemic sibutramine is disclosed, for example, in U.S.Pat. No. 5,436,272.

Sibutramine is rapidly absorbed from the gastrointestinal tractfollowing oral administration and undergoes an extensive first-passmetabolism that yields the metabolites desmethylsibutramine (“DMS”) anddidesmethylsibutramine (“DDMS”), as shown below in Scheme 1.

Both didesmethylsibutramine and desmethylsibutramine have interestingand useful biological properties. Each of these sibutramine metabolitescan exist as an enantiomeric pair of R and S enantiomers, as shown belowin Scheme II, which also exhibit interesting and useful biologicalproperties:

The preparation of enantiomerically pure metabolites of sibutramine andderivatives thereof (e.g., didesmethylsibutramine) has been difficult.Consequently, a need exists for improved methods of synthesis.

Several methods of preparing amine stereoisomers are known in the art.One general method comprises asymmetric addition to an imine, such as byreduction (which adds hydrogen atoms to the carbon and nitrogen atoms atthe ends of the C═N double bond) or by reaction with a source of anucleophile (which adds hydrogen to the nitrogen atom and thenucleophile to the carbon atom). For example, when the source of anucleophile is a source of a nitrile, such as HCN, the reaction affordsan amine stereoisomer in which hydrogen is added to the nitrogen atomand CN to the carbon atom. The nitrile group may then be hydrolyzed toafford an alpha-substituted amino acid stereoisomer.

One such method that has been reported, for example in Liu et al., J.Am. Chem. Soc., 1997, 119, 9913-9914, comprises addition to asulfmylimine stereoisomer that bears on the sulfinyl group a residue ofa hydrocarbyl group, such as p-toluyl or tert-butyl. The resultantsulfinylimine may then be treated with a reagent suitable for thecleavage of a sulfur-nitrogen bond, such as hydrochloric acid, to affordan amine stereoisomer. The sulfinylimine stereoisomers startingmaterials may be obtained by reacting a carbonyl compound, such as analdehyde of ketone, with a sulfinamide stereoisomer, such as ap-toluenesulfinamide or tert-butanesulfinanide stereoisomer.

A novel method of preparing amine stereoisomers has now been found thatstarts with a sulfinylimine that bears on the sulfinyl group a residueof an alcohol, thiol or amine.

According to one aspect, therefore, the present invention provides amethod of preparing an amine stereoisomer, which comprisesstereoselectively reducing a sulfinylimine that bears on the sulfinylgroup a residue of an alcohol, thiol or amine, or reacting asulfinylimine stereoisomer that bears on the sulfinyl group a residue ofan alcohol, thiol or amine with a source of a nucleophile, to afford asulfinylamine stereoisomer, followed by contacting the sulfinylaminestereoisomer with a reagent suitable for the cleavage of asulfur-nitrogen bond, to afford an amine stereoisomer.

It will be appreciated that reduction of the sulfinylimine affords asulfinylamine stereoisomer when the sulfinylimine starting material is asulfinylimine stereoisomer, or when the reduction is performed using astereoselective reducing agent. When a sulfinylimine is reduced,hydrogen atoms are added to the nitrogen and carbon atoms of the iminegroup. When a sulfinylimine stereoisomer is reacted with a source of anucleophile, a hydrogen atom is added to the nitrogen atom and thenucleophile to the carbon atom. Examples of sources of nucleophilesinclude nitriles, Grignard reagents and organolithiums.

In one embodiment of the invention, the sulfinylimine is a sulfinyliminestereoisomer. The residue of the alcohol, thiol or amine may also be instereoisomeric form.

Particular mention is made of sulfinylimines that bear a residue of analcohol on the sulfinyl group, especially those wherein the residue ofthe alcohol is a residue of an optionally N-substitutedbeta-aminoalcohol, thiol or amine, in particular an optionallyN-substituted beta-aminoalcohol.

In one embodiment, the N-substituted beta-aminoalcohol, thiol or aminemay be represented by the general formula

wherein A₁ is R₇N or (R_(7′))R_(7″)N, R₇ represents hydrogen or-L-R_(7a) in which -L- represents a bond, —CO—, —(CO)O—, —(CO)NR_(7b)—,—SO—, —SO₂—, or —(SO₂))O—, each of R_(7a) and R_(7b) independentlyrepresents substituted or unsubstituted alkyl, substituted orunsubstituted aralkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl, and R_(7′) and R_(7″) are as defined for R_(7a), or R_(7′)and R_(7″) together with the nitrogen atom to which they are attachedand, optionally R₈, form an unsubstituted or substituted heterocyclicgroup, or R_(7′) together with the nitrogen atom to which it is attachedand the carbon atom to which the nitrogen atom is attached forms anunsubstituted or substituted heterocyclic group; A₂ is O, S or NR_(7c)in which R_(7c) is substituted or unsubstituted alkyl, substituted orunsubstituted aralkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl; and each of R₈, R₉, R₁₀ and R₁₁ is independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedaralkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl, or R₈ andR₁₁ together form a substituted or unsubstituted alkylene orheteroalkylene chain.

By way of illustration, an example of a compound in which R_(7′) andR_(7″) together with the nitrogen atom to which they are attached and,optionally R₈, form an unsubstituted or substituted heterocyclic groupis quinidine. An example of a compound in which R_(7′) together with thenitrogen atom to which it is attached and the carbon atom to which thenitrogen atom is attached forms an unsubstituted or substitutedheterocyclic group is the compound of formula

The residue of the alcohol, thiol or amine is preferably a residue of analcohol (A₂ is O).

R₇ may represent, for example, —SO₂—R_(7a).

Examples of particular values for R_(7a) are (1-6C)alkyl,(6-10C)aryl(1-4C)alkyl or (6-10C)aryl in which any aryl group isunsubstituted or substituted by one, two or three substituents selectedindependently from halogen, (1-4C)alkyl and (1-4C)alkoxy.

Thus, examples of particular values for R₇ are methanesulfonyl andp-toluenesulfonyl.

Examples of particular values for R_(7′) are (1-4C)alkyl groups, such asmethyl or butyl.

Examples of particular values for R_(7″) are (1-4C)alkyl groups, such asmethyl or butyl.

Examples of particular values where R_(7′), R_(7″) and the nitrogen atomto which they are attached form an unsubstituted or substitutedheterocyclic group are pyrrolidine groups that optionally bear one ortwo methyl substituents, such as pyrrolidinyl, 2-methylpyrrolidinyl and2,5-dimethylpyrrolidinyl.

Examples of compounds containing groups in which R_(7′), R_(7″), R₈, andthe nitrogen atom to which they are attached form an unsubstituted orsubstituted heterocyclic group are quinine, quinidine, cinchonidine,cinchonine, hydroquinine, hydrocinchonidine and ethyl hydrocupreine.

Examples of particular values for R₈ are hydrogen, (1-4C)alkyl, such asmethyl or ethyl, and phenyl.

Examples of particular values for R₉ are hydrogen, (1-4C)allyl, such asmethyl or ethyl, and phenyl.

Examples of particular values for R₁₀ are hydrogen, (1-4C)alkyl, such asmethyl or ethyl, and phenyl.

Examples of particular values for R₁₁ are hydrogen, (1-4C)alkyl, such asmethyl or ethyl, and phenyl.

Examples of beta-aminoalcohols wherein A₁ is R₇N are optionallyN-substituted 2-amino-1-phenylpropanols,2-amino-2-methyl-1-phenylpropanols, 1-amino-1-phenyl-2-propanols,1-amino-1-phenyl-2-methyl-2-propanols,1-amino-1-phenyl-2-ethyl-2-butanols, 1-amino-2-indanols,2-amino-1-indanols, 1-amino-2-hydroxy-1,2,3,4-tetrahydronaphthalenes and2-amino-1-hydroxytetrahydronaphthalenes.

Examples of beta-aminoalcohols wherein A₁ is (R_(7′))R_(7″)N are2-N,N-dimethylamino-1-phenylpropanol,2-N,N-dibutylamino-1-phenylpropanol, 2-pyrrolidin-1-yl-1-phenylpropanol,2-(2-methylpyrrolidin-1-yl)-1-phenylpropanol,2-(2,5-dimethylpyrrolidin-1-yl)-1-phenylpropanol, 2-N,N-dimethylarino-2-methyl-1-phenylpropanol,(N-methylpyrrolidin-2-yl)diphenylnethanol, 1-pyrrolidin-1-ylindan-2-ol,3-benzyloxy-2-N,N-dimethylamino-1-phenylpropan-2-ol, quinine, quinidine,hydroquinine, cinchonidine, cinchonine, hydrocinchonidine or ethylhydrocupreine.

Structures of representative beta-aminoalcohols are as follows.

It has been found that especially high stereoselectivity is associatedwith A₁ is (R_(7′))R_(7″)N. Accordingly, a preference may be expressedfor A₁ is (R_(7′))R_(7″)N.

Compounds derived from beta-aminoalcohols such as quinine correspondwith an alcohol in which R₁₁ is unsubstituted or substitutedquinolin-4-yl. Accordingly, it is contemplated that alternative examplesof particular values for R₁₁ are quinolin-4-yl which is unsubstituted orsubstituted by one or two substituents selected independently from(1-4C)alkyl, (1-4C)alkoxy and halogen.

Sulfinylimines that bear on the sulfinyl group a residue of an alcohol,thiol or amine may be prepared by reacting an iminometal, such as animinomagnesium chloride, with a compound of formula Z′-SO—R in which Z′represents a leaving atom or group, such as a fluorine, chlorine orbromine atom, and R represents a residue of an alcohol, thiol or amine.

Sulfinylimines in which the sulfinyl group bears a residue of anoptionally N-substituted beta-aminoalcohol, thiol or amine mayadvantageously be prepared by contacting an iminometal, such as anininomagnesium chloride, with a 1,2,3-oxathiazolidine-S-oxide,1,2,3-dithiazolidine-S-oxide or 1,2,3-azathiazolidine respectively.

According to a preferred aspect, therefore, the sulfmylirnine used inthe method has been prepared by contacting an iminometal with a1,2,3-oxathiazolidine-S-oxide, 1,2,3-dithiazolidine-S-oxide or1,2,3-azathiazolidine-S-oxide respectively, especially a1,2,3-oxathiazolidine-S-oxide, 1,2,3-dithiazolidine-S-oxide or1,2,3-azathiazolidine-S-oxide stereoisomer (which affords asulfinylimine stereoisomer in which the sulfinyl group bears a residueof an optionally N-substituted beta-aminoalcohol, thiol or amine also instereoisomeric form). 1,2,3-Oxathiazolidine-S-oxides,1,2,3-dithiazolidine-S-oxides and 1,2,3-azathiazolidine-S-oxides may beprepared by reacting respectively an optionally N-substitutedbeta-aminoalcohol, thiol or amine with a sulfonyl halide, such asthionyl chloride in the presence of an amine base, such as a pyridinederivative.

The 1,2,3-oxathiazolidine-S-oxide, 1,2,3-dithiazolidine-S-oxide or1,2,3-azathiazolidine-S-oxide may be, for example, a compound of formula3 or 3′

wherein A₁ is R₇N or (R_(7′))R_(7″)N⁺ Q⁻ in which Q− is an anion, R₇represents hydrogen or -L-R_(7a) in which -L- represents a bond, —CO—,—(CO)O—, —(CO)NR_(7b)—, —SO—, —SO₂—, or —(SO₂)O—, each of R_(7a) andR_(7b) independently represents substituted or unsubstituted alkyl,substituted or unsubstituted aralkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl, and R_(7′) and R_(7″) are as defined forR_(7a), or R_(7′) and R_(7″) together with the nitrogen atom to whichthey are attached and, optionally R₈, form an unsubstituted orsubstituted heterocyclic group, or R_(7′) together with the nitrogenatom to which it is attached and the carbon atom to which the nitrogenatom is attached forms an unsubstituted or substituted heterocyclicgroup; A₂ is O, S or NR_(7c) in which R_(7c) is substituted orunsubstituted alkyl, substituted or unsubstituted aralkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted aryl orsubstituted or unsubstituted heteroaryl; and each of R₈, R₉, R₁₀and R₁₁is independently hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted aralkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl, or R₈ and R₁₁ together form a substituted orunsubstituted alcylene or heteroalkylene chain.

The iminometal may be, for example, a compound of formula 1′

wherein M is CdZ, BaZ, Na, K, MgZ, ZnZ, Li, MnZ, CuZ, TiZ₃ or In and Zis an anion.

When the sulfinylamine has been prepared from a sulfinylimine in whichthe sulfinyl group bears the residue of an optionally N-substitutedbeta-aminoalcohol, thiol or amine, treatment of the sulfinylamine with areagent suitable for the cleavage of a sulfur-nitrogen bond, such as anacid, affords as a second reaction product the optionally N-substitutedbeta-aminoalcohol, thiol or amine. This alcohol, thiol or amine mayadvantageously be recycled by converting it into1,2,3-oxathiazolidine-S-oxide, 1,2,3-oxadiathiazolidine-S-oxide or1,2,3-azathiazolidine-S-oxide. According to a preferred aspecttherefore, the method further comprises recovering optionallyN-substituted beta-aminoalcohol, thiol or amine, converting this into1,2,3-oxathiazolidine-S-oxide and reacting this with an iminometal asdescribed hereinabove.

A sulfinylimine may be reduced to a sulfinylamine stereoisomer using anysuitable reducing agent. Thus, it will be appreciated that the reducingagent may be any reducing agent capable of reducing a sulfinylimine to asulfinylamine, provided that if the sulfinylimine is not a sulfinyliminestereoisomer, then the reducing agent is a stereoselective reducingagent. Examples of reducing agents include hydrogen, in the presence ofa group VIII metal catalyst, such as palladium on carbon; boranes;hydrogen transfer reagents, such as cyclohexene and formic acid in thepresence of palladium on carbon, and hydride-type reducing agents.

Examples of stereoselective reducing agents include asymmetrichydrogenation agents, asymmetric transfer hydrogenation reagents andasymmetric oxazaborolidine agents.

Examples of asymmetric hydrogenation agents are described in Burk M J,Allen J G, Kiesman W F: Highly regio- and enantioselective catalytichydrogenation of enamides in conjucated diene systems: Synthesis andapplication of γ,δ-unsaturated amino acids. J. Am. Chem. Soc (1998)120:657-663; Burk M J, Casy G, Johnson N B: A three-step procedure forasymmetric catalytic reductive amidation of ketones. J. Org. Chem (1998)63:6084-6085; hang F-Y, Pai C-C, Chan A S C: Asymmetric synthesis ofchiral amine derivatives through enantioselective hydrogenation with ahighly effective rhodium catalyst containing a chiral bisaminophosphineligand. J. Am. Chem. Soc (1998) 120:5808; and Doucet H, Ohkuma T, MurataK, Yokozawa T, Kozawa M, Katayama E, England A F, Ikariya T, Noyori N:trans-[RuCl₂(phosphane)₂(1,2-diamine)] and chiraltrans-[RuCl₂(phosphane) (1,2-diamine)]: Shelf-stable precatalysts forthe rapid, productive, and stereoselective hydrogenation of ketones.Angew. Chem. Int. Ed (1998) 37:1703-1707.

Examples of asymmetric transfer hydrogenation reagents are described inMurata K, Ikariya T, Noyori R: New chiral Rhodium and Iridium complexeswith chiral diamine ligands for asymmetric transfer hydrogenation ofaromatic ketones. J. Org. Chem (1999) 64:2186-2187 and references citedtherein.

Examples of asymmetric oxazaborolidine agents are described in Hett R,Senanayake C H, Wald S A: Conformational toolbox of oxazaborolidinecatalysts in the enantioselective reduction of α-bromo-ketone for thesynthesis of (R,R)-formoterol. Tetrahedron Lett. (1998) 39:1705-1708 andreferences cited therein.

A preferred reducing agent is a hydride type reducing agent, for examplean alkali metal (lithium, sodium or potassium) aluminium hydride orborohydride. The aluminium or boron atoms may be unsubstituted orsubstituted by one, two or three substituents, such as alkyl, alkoxy oraryl group, sodium borohydride, lithium aluminium hydride, lithiumborohydride, lithium triethylborohydride, diisobutylaluminium hydride,lithium trimethoxyaluminium hydride or sodium bis(2-methoxy)aluminiumhydride. Particular mention may be made of sodium borohydride.

The reduction is conveniently performed at a temperature in the range offrom −75 to 25° C. Convenient solvents include halogenated hydrocarbons,such as dichloromethane, ethers, such as diethyl ether, methyl t-butylether (MTBE) or tetrahydrofuran and alcohols such as methanol orethanol. Particular mention may be made of ethers, especiallytetrahydrofuran. The reduction with the hydride type reducing agent maybe performed in the presence of a Lewis acid, such as boron trifluoride,a titanium tetra(1-4C)alkoxide, such as titanium tetraethoxide, titaniumtetrapropoxide, titanium tetraisopropoxide; a titanium tetrahalide, suchas titanium tetrachloride; a zirconium tetra(1-4C)alkoxide, such aszirconium tetraethoxide or zirconium tetra-t-butoxide; a zinc dihalide,such as zinc dichloride, or a magnesium dihalide, such as magnesiumdibromide. Particular mention may be made of titaniumtetra(1-4C)alkoxides, for example used with sodium borohydride.

The reagent suitable for cleavage of a sulfur-nitrogen bond may be, forexample, an acid. Examples of acids include hydrohalic acids, such ashydrochloric acid; sulfonic acids, such as p-toluenesulfonic acid;pyridinium sulfonates, such as pyridium-p-toluenesulfonate; AmberlystH-15, boric acid and acetic acid. Particular mention may be made ofhydrochloric acid. The cleavage of the sulfur-nitrogen bond isconveniently performed at a temperature in the range of from −50 to 50°C.

Examples of biologically active amine stereoisomers include thestereoisomers of Alacepril, Benazepril, Benazeprilate, Ceronapril,Cilazapril, Cilazaprilat, Delapril, Enalapril, Enalaprilat, Fasidotril,Fosinopril, Imidapril, Imidaprilat, Libenzapril, Lisinopril, Moexipril,Moexiprilat, Moveltipril, Pentopril, Perindopril, Quinapril,Quinaprilat, Ramipril, Sampatrilat, Spirapril, Spiraprilat, Temocapril,Temocaprilate, Trandolapril, Trandolaprilate, Utibapril, Utibaprilat,Zabicipril, Zabiciprilat, Bucillamine, Penicillamine, Thiamphenicol,Cefprozil, Cephalexin, Cephaloglycin, Cilastatin, Alafosfalin,Ethambutol, Sertraline, Tametraline, Acetylcysteine, Selegiline,Azaserine, Dorzolamide, Colchicine, Dilevalol, Enalapril, Methyldopa,Metaraminol, Acivicin, Melphalan, Ubenimex, Tmsulosin, Tirofiban,Dilevalol, N-dodecyl-N-methylephedrinium, Ofenucine, Tinofedrine,Aceglutamide, 1-ephedrine, levopropylhexedrine, (+)-and(−)-Norephedrine, Phenylpropanolamine, Pseudoephedrine, d-farm, (R)— and(S)-Tamsulosin, Dimepheptanol, Lofentanil, Tilidine hydrochloride(+)-trans, Ciramadol, Enadoline, Lefetamine, Spiradoline, (+)-Etoxadrol,Levoxadrol, (R)-Amphetamine, Clobenzorex, Dexfenfluramine,Dextroamphetamine, Etilamfetamine, Fenfluramine, Levofenfluramine,Phenylpropanolamine, Cetirzine, (R)— and (S)-Baclofen, (R)— and(S)-Sibutramine, and pharmaceutically acceptable salts thereof.

In one embodiment, the amine stereoisomer is a compound of formula 5 or5′

or a pharmaceutically acceptable salt, solvate, clathrate, hydrate orprodrug thereof, wherein R₅ and R₆ are independently substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aralkyl, substituted or unsubstituted arylor substituted or unsubstituted heteroaryl, or R₅ and R₆ together withthe carbon atom to which they are attached form a substituted orunsubstituted cycloalkyl group, and R₁₂ and R₁₃ together with thenitrogen atom to which they are attached form a heterocycle, or each ofR₁₂ and R₁₃ is independently hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted aralkyl, or substituted orunsubstituted aryl, and the sulfinylamine stereoisomer is a compound offormula 4 or 4′

wherein A_(1′) represents R₇N or (R_(7′))R_(7″)N.

An example of a value for A₂ is O.

According to another aspect, the present invention provides a compoundof formula

wherein:

-   -   R₅ and R₆ are independently substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted aralkyl, substituted or unsubstituted aryl or        substituted or unsubstituted heteroaryl, or R₅ and R₆ together        with the carbon atom to which they are attached form a        substituted or unsubstituted cycloalkyl group;    -   A₁ is R₇N or (R_(7′))R_(7″)N;    -   R₇ represents hydrogen or -L-R_(7a) in which -L- represents a        bond, —CO—, —(CO)O—, —(CO)NR_(7b)—, —SO—, —SO₂—, or —(SO₂)O—,        each of R_(7a) and R_(7b) independently represents substituted        or unsubstituted alkyl, substituted or unsubstituted aralkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted aryl or substituted or unsubstituted heteroaryl,        and R_(7′) and R_(7″) are as defined for R_(7a), or R_(7′) and        R_(7″) together with the nitrogen atom to which they are        attached and, optionally R₈, form an unsubstituted or        substituted heterocyclic group, or R₇, together with the        nitrogen atom to which it is attached and the carbon atom to        which the nitrogen atom is attached forms an unsubstituted or        substituted heterocyclic group; A₂ is O, S or NR_(7c) in which        R_(7c) is substituted or unsubstituted alkyl, substituted or        unsubstituted aralkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl; and each of R₈, R₉, R₁₀ and R₁₁ is        independently hydrogen, substituted or unsubstituted alkyl,        substituted or unsubstituted aralkyl, substituted or        unsubstituted heteroalkyl, substituted or unsubstituted aryl or        substituted or unsubstituted heteroaryl, or R₈ and R₁₁ together        form a substituted or unsubstituted alkylene or heteroalkylene        chain;    -   A₂ is O, S or NR_(7c) in which R_(7c) is substituted or        unsubstituted alkyl, substituted or unsubstituted aralkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted aryl or substituted or unsubstituted heteroaryl;        and    -   each of R₈, R₉, R₁₀ and R₁₁ is independently hydrogen,        substituted or unsubstituted alkyl, substituted or unsubstituted        aralkyl, substituted or unsubstituted heteroaLkyl, substituted        or unsubstituted aryl or substituted or unsubstituted        heteroaryl, or R₈ and R₁₁ together form a substituted or        unsubstituted alkylene or heteroalkylene chain,    -   or a salt thereof.

According to yet another aspect, the present invention provides acompound of formula

wherein A₁ is (R₇)R_(7′)N⁺ Q⁻ in which Q− is an anion and each of R₇ andR_(7′) independently represents substituted or unsubstituted alkyl,substituted or unsubstituted aralkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl, or two substituents R₇ together with thenitrogen atom to which they are attached and, optionally R₈, form anunsubstituted or substituted heterocyclic group, or one R₇ substituenttogether with the nitrogen atom to which it is attached and the carbonatom to which the nitrogen atom is attached form an unsubstituted orsubstituted heterocyclic group; A₂ is O, S or NR_(7c) in which R_(7c) issubstituted or unsubstituted alkyl, substituted or unsubstitutedaralkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl; and eachof R₈, R₉, R₁₀ and R₁₁ is independently hydrogen, substituted orunsubstituted alkcyl, substituted or unsubstituted aralkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted aryl orsubstituted or unsubstituted heteroaryl, or R₈ and R₁₁ together form asubstituted or unsubstituted alkylene or heteroalkylene chain, or a saltthereof.

Compounds of formula 3″ are also useful in a method of preparingsulfinamide stereoisomers, such as the stereoisomers oft-butylsulfinamide.

According to yet another aspect therefore, the present inventionprovides a method of preparing a sulfinamide stereoisomer, whichcomprises reacting a compound of formula 3″ as defined hereinabove witha first organtometallic reagent of formula R¹M to afford a compound offormula

and then either reacting this compound with a second organometallicreagent of formula R²M to afford a sulfoxide stereoisomer of formulaR¹—SO—R²in which R¹ and R² each independently represents an organic group, orwith an alkali metal amide to afford a sulfinylamine stereoisomer.

The choice of suitable first and second organometallic reagents andamides, and suitable reaction conditions, will be readily apparent tothose skilled in the art. The suitable reagents include Grignardreagents, organolithium reagents, organocopper reagents andorganoaluminium reagents. An example of a first or second organometallicreagent is an organomagnesium halide, such as an alkyl or arylmagnesiumhalide. Examples of an amide are lithium amide and lithiumhexamethylenedisilylamide. Examples of uses of these reagents aredescribed in the examples herein. Particularly good results have beenobtained using compounds of formula 3″ that are derived from quinine.

As used herein, the term “prodrug” means a derivative of a compound thatcan hydrolyze, oxidize, or otherwise react under biological conditions(in vitro or in vivo) to provide the compound. Examples of prodrugsinclude, but are not limited to, derivatives of desmethylsibutramine anddidesmethylsibutramine that comprise biohydrolyzable moieties such asbiohydrolyzable amides, biohydrolyzable esters, biohydrolyzablecarbamates, biohydrolyzable carbonates, biohydrolyzable ureides, andbiohydrolyzable phosphate analogues. Other examples of prodrugs includederivatives of desmethylsibutramine and didesmethylsibutramine thatcomprise —NO, —NO₂, —ONO, and —ONO₂ moieties. As used herein, prodrugsof didesmethylsibutramine do not include desmethylsibutramine orsibutramine, and prodrugs of desmethylsibutramine do not includesibutramine.

As used herein, the terms “biohydrolyzable carbamate,” “biohydrolyzablecarbonate,” “biohydrolyzable ureide,” “biohydrolyzable phosphate” mean acarbamate, carbonate, ureide, or phosphate, respectively, of a compoundthat either: 1) does not interfere with the biological activity of thecompound but can confer upon that compound advantageous properties invivo, such as uptake, duration of action, or onset of action; or 2) isbiologically less active or inactive but is converted in vivo to thebiologically active compound. Examples of biohydrolyzable carbamatesinclude, but are not limited to, lower alkylamines, substitutedethylenediamines, aminoacids, hydroxyalkylamines, heterocyclic andheteroaromatic amines, and polyether amines.

As used herein, the term “biohydrolyzable ester” means an ester of acompound that either: 1) does not interfere with the biological activityof the compound but can confer upon that compound advantageousproperties in vivo, such as uptake, duration of action, or onset ofaction; or 2) is biologically less active or inactive but is convertedin vivo to the biologically active compound. Examples of biohydrolyzableesters include, but are not limited to, lower alkyl esters,alkoxyacyloxy esters, alkyl acylamino alkyl esters, and choline esters.

As used herein, the term “biohydrolyzable amide” means an amide of acompound that either: 1) does not interfere with the biological activityof the compound but can confer upon that compound advantageousproperties in vivo, such as uptake, duration of action, or onset ofaction; or 2) is biologically less active or inactive but is convertedin vivo to the biologically active compound. Examples of biohydrolyzableamides include, but are not limited to, lower alkyl amides, a-amino acidamides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides.

As used herein, the term “pharmaceutically acceptable salt” refers to asalt prepared from a pharmaceutically acceptable non-toxic inorganic ororganic acid. Suitable non-toxic acids include, but are not limited to,acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethenesulfonic, flimaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfiric, tartaric,and p-toluenesulfonic acids. For example, specific pharmaceuticallyacceptable salts are hydrochloride, maleic acid, and tartaric acidsalts.

As used herein and unless otherwise indicated, the term “alkyl” includessaturated monovalent linear, branched, and cyclic hydrocarbon radicals.An alkyl group can include one or more double or triple bonds. It isunderstood that cyclic alkyl groups comprise at least three carbonatoms.

As used herein and unless otherwise indicated, the term “heteroalkyl”means branched or linear alkyl having from 1 to 8, more preferably from1 to 4 carbon atoms and including at least one heteroatom, including N,P, O, or S. Examples include, but are not limited to, compounds of theformula:

wherein X is O, P, NH, or S.

As used herein and unless otherwise indicated, the term “lower alkyl”means branched or linear alkyl having from 1 to 6, more preferably from1 to 4 carbon atoms. Examples include, but are not limited to, methyl,ethyl, propyl, isopropyl, isobutyl, and tertiary butyl.

As used herein and unless otherwise indicated, the term “aryl” includesan organic radical derived from an aromatic hydrocarbon by removal ofone hydrogen, such as phenyl or naphthyl.

As used herein and unless otherwise indicated, the term “aralkyl” meansan aryl substituted with one or linear, branched, or cyclic alkylgroups. Aralkyl moieties can be attached to other moieties through theiraryl or alkyl components.

As used herein and unless otherwise indicated, the terms “heterocyclicgroup” and “heterocycle” include aromatic and non-aromatic heterocyclicgroups containing one or more heteroatoms each selected from O, S and N.Non-aromatic heterocyclic groups include groups having only 3 atoms intheir ring system, but aromatic heterocyclic groups (i.e., heteroarylgroups) must have at least 5 atoms in their ring system. Heterocyclicgroups include benzo-fased ring systems and ring systems substitutedwith one or more oxo moieties. An example of a 4 membered heterocyclicgroup is azetidinyl (derived from azetidine). An example of a 5 memberedheterocyclic group is thiazolyl, and an example of a 10 memberedheterocyclic group is quinolinyl. Examples of non-aromatic heterocyclicgroups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl,tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidino,morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl,oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl,diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl,3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl,dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl,imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl,3H-indolyl, quinolizinyl, and substituted derivative thereof. Examplesof aromatic heterocyclic groups include, but are not limited to,pyridinyl, methylpyridine analgoues, imidazolyl, pyrimidinyl, pyrazolyl,triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, benzoimidazoles, benzofuranyl, cinnolinyl, indazolyl,indolinyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl,isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl,benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl,quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, andsubstituted derivatives thereof The foregoing groups, as derived fromthe compounds listed above, may be C-attached or N-attached where suchattachment is possible. For instance, a group derived from pyrrole canbe pyrrol-1-yl N-attached) or pyrrol-3-yl (C-attached).

As used herein and unless otherwise indicated, the term “heteroaryl”means an aromatic heterocycle.

As used herein and unless otherwise indicated, the term “substituted” asused to describe a compound or chemical moiety means that at least onehydrogen atom of that compound or chemical moiety is replaced with asecond chemical moiety. Examples of second chemical moieties include,but are not limited to: halogen atoms (e.g., chlorine, bromine, andiodine); C₁-C₆ linear, branched, or cyclic alkyl (e.g., methyl, ethyl,butyl, tert-butyl, and cyclobutyl); hydroxyl; thiols; carboxylic acids;esters, amides, silanes, nitrites, thioethers, stannanes, and primary,secondary, and tertiary amines (e.g., —NH₂, —NH(CH₃), —N(CH₃)₂, andcyclic arines). Preferred second chemical moieties are chlorine,hydroxyl, methoxy, amine, thiol, and carboxylic acid.

As used herein and unless otherwise indicated, a composition that is“substantially free” of a compound means that the composition containsless than about 20% by weight, more preferably less than about 10% byweight, even more preferably less than about 5% by weight, and mostpreferably less than about 3% by weight of the compound.

As used herein and unless otherwise indicated, the term “stereomericallypure” means a composition that comprises one stereoisomer of a compoundand is substantially free of other stereoisomers of that compound. Forexample, a stereomerically pure composition of a compound having onechiral center will be substantially free of the opposite enantiomer ofthe compound. A stereomerically pure composition of a compound havingtwo chiral centers will be substantially free of other diastereomers ofthe compound. A typical stereomerically pure compound comprises greaterthan about 80% by weight of stereoisomer of the compound and less thanabout 20% by weight of other stereoisomers the compound, more preferablygreater than about 90% by weight of one stereoisomer of the compound andless than about 10% by weight of the other stereoisomers of thecompound, even more preferably greater than about 95% by weight of onestereoisomer of the compound and less than about 5% by weight of theother stereoisomers of the compound, and most preferably greater thanabout 97% by weight of one stereoisomer of the compound and less thanabout 3% by weight of the other stereoisomers of the compound.

As used herein and unless otherwise indicated, the term“enantiomerically pure” means a stereomerically pure composition orcompound.

As used herein, compounds encompassed by the term“1,2,3-oxathiazolidine-S-oxides, 1,2,3-dithiazolidine-S-oxides,1,2,3-azadithiazoline-S-oxides and derivatives thereof” are generally ofthe formula:

Corresponding iminosulfonates obtainable by reaction of these compoundswith an iminometal are of the formula

Corresponding optionally N-substituted beta-aminoalcohols, thiols andamines are represented by the formulae:

In this embodiment, particular mention is made a method in which A₂ isO, R₅ and R₆ are independently substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedaralkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl; the 1,2,3-oxathiazolidine-S-oxide is acompound of the formula 3 or 3′

in which R₇ represents hydrogen or -L-R_(7a) in which L represents abond or SO₂ and R_(7a) represents substituted or unsubstituted alkyl,substituted or unsubstituted aralkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl; Z in the iminometal of formula 1′ is Cl, Br orI.; and the sulfinylamine stereoisomer is a compound of formula

In a preferred embodiment, the term “1,2,3-oxathiazolidine-S-oxides andderivatives thereof” encompasses compounds of the formula:

It should be noted that if there is a discrepancy between a depictedstructure and a name given that structure, the depicted structure is tobe accorded more weight. In addition, if the stereochemistry of astructure or a portion of a structure is not indicated with, forexample, bold or dashed lines, the structure or portion of the structureis to be interpreted as encompassing all stereoisomers of it.

A first embodiment of the invention encompasses a method of preparingchiral amines of formulas 5 or 5′:

or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, orprodrug thereof, wherein R₅ and R₆ are independently substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aralkyl, or substituted or unsubstitutedaryl.

The method of preparing chiral amines of formula 5: or apharmaceutically acceptable salt, salyate, clathrate, hydrate, orprodnig thereof,

wherein R₅ and R₆ are independently substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedaralkyl, substituted or unsubstituted heteroalkyl, or substituted orunsubstituted aryl, comprises contacting a compound of Formula 3:

with a compound of formula 1′:

wherein under conditions suitable for the formation of a compound offormula 4:

followed by hydrogenation and work-up under conditions suitable for thecleavage of a sulfur-nitrogen bond and for the formation of astereomerically pure amine. In an optional embodiment, the aminecompound of formula 5 is treated with an alkylating agent (e.g., alkyliodide) under conditions suitable for the formation of mono- ordi-alkylated amines of formula 5′ and 5″:

wherein R₁₂ and R₁₃ is independently substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedaralkyl, or substituted or unsubstituted aryl.

In another embodiment, the amine compound of formula 5 is optionallytreated with a methylating agent (e.g., methyl iodide) under conditionssuitable for the formation of mono- or di-methylated amines of formula6′ and 6″:

One of ordinary skill in the art will readily recognize that compoundsof formula 5′ can be prepared by following the above procedure butreplacing compound 3 with compound 3′:

A second embodiment of the invention encompasses a method of preparing acompound of Formula 7:

or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, orprodrug thereof, wherein R₁₄ is substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedaralkyl, or substituted or unsubstituted aryl, and R₁₅ and R₁₆ togetherwith the nitrogen atom to which they are attached form a heterocycle, oreach of R₁₅ and R₁₆ is independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aralkyl, or substituted or unsubstitutedaryl, which comprises contacting a compound of Formula 8:

wherein M is CdZ, BaZ, Na, K, MgZ, ZnZ, Li, MnZ, CuZ, TiZ₃, or In, and Zis Cl, Br, I, aryl, aralkyl, alkoxy, or heterocycle with a compound offormula 3:

under conditions suitable for the formation of a compound of formula 9:

followed by hydrogenation and work-up under conditions suitable for thecleavage of a sulfur-nitrogen bond and for the formation of astereomerically pure amine of formula 7. In another embodiment, thecompound of formula 7 is treated with D-tartaric acid under conditionssuitable for the formation of a compound of formula 10:

One of ordinary skill in the art will readily recognize that compoundsof formula 7′ can be prepared by following the above procedure butreplacing compound 3 with

compound 3′:

In a preferred method, the compounds of formulas 5, 6, 7, and 10 arestereomerically pure. In another preferred method, the compounds ofFormula 5, 6, and 7 are provided as a pharmaceutically acceptable salt.Examples of preferred pharmaceutically acceptable salts include, but arenot limited to, acetic, benzenesulfonic, benzoic, camphorsulfonic,citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic,hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric, and p-toluenesulfonic salts.

In another preferred method, the reagent capable of cleaving anitrogen-sulfur bond is an acid. A preferred acid is HCl.

The compound of Formulas 5 or 7, respectively, can be prepared bycontacting a compound of Formula 4 or 9:

with a Lewis acid and a compound of the formula RM, wherein R is analkyl, aryl, or arylalkyl and M is Cdz, BaZ, Na, K, MgZ, Znz, Li, MnZ,CuZ, TiZ₃, or In, and Z is Cl, Br, I, aryl, aralkyl, alkoxy, orheterocycle under conditions suitable for the formation of the compoundof Formula 5 or 7.

The compound of Formula 1′ can be prepared by contacting a compound ofFormula 11:R₆—CN   11with a compound of formula 12:R₅—M   12under conditions suitable for the formation of a compound of formula 1′:

Compounds of formula 12 are generally formed by treating a compound offormula 13:R₅—Hal   13with a metal or Lewis acid under conditions suitable for the formationof a compound of formula 12. Metals used to generate compounds offormula 12 include, but are not limited to CdZ, BaZ, Na, K, MgZ, ZnZ,Li, MnZ, CuZ, TiZ₃, or In, wherein Z is Cl, Br, aryl, aralkyl, alkoxy,or heterocycle. Examples of Lewis acids include, but are not limited to,BF₃OEt₂, SnCl₄, Sc(OTf)₂, Al(alkyl)₃, Ti(alkyl)₄, Ti(alkoxy)₄, TiCl₄,Zn(OTf)₂, Mg(OTf)₂, TiHal_(k)(O-i-Pr)_(4-k) (wherein Hal is F, Cl, Br,or I, and k is 1, 2, or 3), and derivatives thereof. Suitable solventsfor obtaining compounds 12 include, but are not limited to,dichloromethane, diethyl ether, tetrahydrofuran, benzene, toluene,xylene, hydrocarbon solvents (e.g., pentane, hexane, and heptane), andmixtures thereof. Preferably, the organic solvent is toluene.

The compound of formula 3:

can be prepared by treating a compound of formula 2:

with thionyl chloride and a base at low temperature, preferably lessthan 0° C., more preferably less than −25° C., and most preferably lessthan −40° C. Preferably, the base is added at a rate such that thereaction-mixture temperature remains within about one to two degrees ofthe initial reaction-mixture temperature. The base can be added as anorganic solution or in undiluted form. Preferably, the base will have abase strength sufficient to deprotonate a proton, wherein the proton hasa pK_(a) of greater than about 15, preferably greater than about 20. Asis well known in the art, the pK_(a) is a measure of the acidity of anacid H-A, according to the equation pK_(a)=−log K_(a), wherein K_(a) isthe equilibrium constant for the proton transfer. The acidity of an acidH-A is proportional to the stability of its conjugate base ⁻A. Fortables listing pK_(a) values for various organic acids and a discussionon pK_(a) measurement, see March, J. Advanced Organic Chemistry;Reactions Mechanisms, and Structure, 4th ed., 1992, pp. 248-272,incorporated herein by reference. Suitable bases include, but are notlimited to, alkylmetal bases such as methyllithium, n-butyllithium,tert-butyllithium, sec-butyllithium, phenyllithium, phenyl sodium, andphenyl potassium; metal amide bases such as lithium amide, sodium amide,potassium amide, lithium tetramethylpiperidide, lithiumdiisopropylamide, lithium diethylamide, lithium dicyclohexylamide,sodium hexamethyldisilazide, and lithium hexamethyldisilazide; andhydride bases such as sodium hydride and potassium hydride. Solventssuitable for reacting compounds 2 with base include, but are notlimited, to dimethyl sulfoxide, dichloro-methane, ethers, and mixturesthereof, preferably tetrahydrofuran.

One of ordinary skill in the art will readily recognize that compoundsof formula 3′:

can be formed by treating a compound of formula 2′:

with thionyl chloride and base under conditions described above.

In a preferred method, the compound of Formula 3 or 3′ isstereomerically pure, as shown below:

A third embodiment of the invention encompasses a method of preparing acompounds of formula 14 and 14′:

and salts, solvates, clathrates, and hydrates thereof, wherein each ofR₁₅ and R₁₆ is described above. In a preferred embodiment, R₁₅ and R₁₆are independently hydrogen or alkyl. In a more preferred embodiment, R₁₅and R₁₆ are independently hydrogen or methyl. In an even more preferredembodiment, R₁₅ and R₁₆ are both hydrogen.

The embodiment of the invention encompasses treating a compound offormula 15:

with a compound of formula i-BuMg-X, wherein X is a halogen, preferablyBr or I, more preferably Br under conditions suitable for the formationof an intermediate of formula:

followed by treating with a compound of formula 3:

under conditions suitable for the formation of a compound of formula 16:

and followed by hydrogenation and work-up under conditions suitable forthe cleavage of a sulfur-nitrogen bond and for the formation of astereomerically pure amine of formula 13 or salts, solvates, clathrates,and hydrates thereof. In a preferred embodiment, the compound of formula3 above has the following structure:

In a preferred method, the compounds of formula 13 are stereomericallypure. In another preferred method, the compounds of Formula 13 areprovided as a pharmaceutically acceptable salt, preferably as a tartaricacid salt. In another embodiment, the method encompasses making acompound of formula 14′:

under conditions set forth above using a compound of formula 3′:

In a preferred embodiment, the compound of formula 3′ has the followingstructure:

5. EXAMPLES

Sibutramine, desmethylsibutramine, didesmethylsibutramine, andderivatives of each can be readily prepared according to the methodrepresented below in Scheme III. This scheme, like others disclosedherein, is merely representative of a method of the invention, and isnot to be construed as limiting its scope in any way.

5.1. PREPARATION OF STEREOMERICALLY PURE 1,2,3-OXATHIAZOLIDINE-S-OXIDES

The synthesis of stereomerically pure (R)— and(S)-1,2,3-oxathiazolidine-S-oxides is described in Scheme 3.

Scheme 3 illustrates the synthesis of R_(s)- andS_(s)-1,2,3-oxathiazolidine-S-oxides in stereomerically pure form.Generally, compounds of formula 3 and 3′ are formed by contactingcompounds of formula 2 or 2′, respectively with thionyl chloride at lowtemperature (e.g., −45° C.) in the presence of a base. The base can beadded as an organic solution or in undiluted form. Preferably, the basewill have a base strength sufficient to deprotonate a proton, whereinthe proton has a pK_(a) of greater than about 15, preferably greaterthan about 20. As is well known in the art, the pK_(a) is a measure ofthe acidity of an acid H-A, according to the equation pK_(a)=−log K_(a),wherein K_(a) is the equilibrium constant for the proton transfer. Theacidity of an acid H-A is proportional to the stability of its conjugatebase A⁻. For tables listing pK_(a) values for various organic acids anda discussion on pK_(a) measurement, see March, J. Advanced OrganicChemistry; Reactions Mechanisms, and Structure, 4th ed., 1992, pp.248-272, incorporated herein by reference. Suitable bases include, butare not limited to, amine bases such as trialkylamine, for exampletriethylamine and pyridine derivatives, such as pyridine, lutidines,collidines and quinoline. Solvents suitable for reacting compounds 2with base include, but are not limited, to dimethyl sulfoxide,dichloro-methane, ethers, and mixtures thereof, preferablytetrahydrofuran.

5.2. PREPARATION OF STEREOMERICALLY PURE IMINES

Stereomerically pure imines can be prepared as shown in Scheme 4.

Compounds 4 and 4′ can generally be prepared by adding a metal-iminecomplex to a compound of formula 3 or 3′, respectively. In particular,compounds of formula 4 and 4′ are generally formed by treating a nitrilewith a metal or Lewis acid under conditions suitable for the formationof a metal imine complex. Metals used to generate compounds of formula1′ include, but are not limited to CdZ, BaZ, Na, K, MgZ, ZnZ, Li, MnZ,CuZ, TiZ₃, or In, wherein Z is Cl, Br, aryl, aralkyl, alkoxy, orheterocycle. Examples of Lewis acids include, but are not limited to,BF₃OEt₂, SnCl₄, Sc(OTf)₂, Al(alkyl)₃, Ti(alkyl)₄, Ti(alkoxy)₄, TiCl₄,Zn(OTf)₂, Mg(OTf)₂, TiHal_(k)(O-i-Pr)_(4-k) (wherein Hal is F, Cl, Br,or I, and k is 1, 2, or 3), and derivatives thereof. Suitable solventsfor obtaining compound 4 and 4′ include, but are not limited to,dichloromethane, diethyl ether, tetrahydrofuran, benzene, toluene,xylene, hydrocarbon solvents (e.g., pentane, hexane, and heptane), andmixtures thereof. Preferably, the organic solvent is toluene.

5.3. REDUCTION OF STEREOMERICALLY PURE IMINES

Stereomerically pure imines can be reduced to stereomerically pureamines as llustrated in Scheme 5.

Scheme 5 illustrates the synthesis of stereomerically pure (R)— and(S)-amine compounds. Next, compounds 4 and 4′ are first treated with areducing agent to reduce the imine to a stereomerically pure amine witha suitable reducing agent. A wide variety of reagents are available forreduction of such esters to alcohols, e.g., see M. Hudlicky, Reductionsin Organic Chemistry, 2nd ed., 1996 pp. 212-217, hereby expresslyincorporated herein by reference. Preferably, the reduction is effectedwith a hydride type reducing agent, for example, sodium borohydride,lithium aluminum hydride, lithium borohydride, lithium triethylborohydride, diisobutylaluminum hydride, lithium trimethoxyaluminumhydride, or sodium bis(2-methoxy)aluminum hydride. Preferably, thereduction is conducted by adding an organic solution of compounds 4 or4′ to a stirred mixture comprising a reducing agent, preferably sodiumborohydride hydride, and an organic solvent. During the addition, thereaction mixture is maintained at a constant temperature within therange of about −20° C. to about 80° C., preferably at about roomtemperature. Organic solvents suitable for reduction include, but arenot limited to, dichloromethane, diethyl ether, tetrahydrofuran ormixtures thereof, preferably tetrahydrofuiran. After the addition, thereaction mixture is stirred at a constant temperature within the rangeof about 0° C. to about −45 ° C., until the reaction is substantiallycomplete as determined by using an appropriate analytical method,preferably thin-layer chromatography or high-performance-liquidchromatography. Then the reaction an acid is added to the reactionmixture to facilitate cleavage of the sulfur-nitrogen bond. Thesulfur-nitrogen bond is preferably cleaved with an acid. Suitablecleavage reagents include, but are not limited to, aqueous hydrochloricacid, p-toluenesulfonic acid in methanol, pyridinium-p-toluenesulfonatein ethanol, Amberlyst H-15 in methanol, boric acid inethylene-glycol-monoethylether, acetic acid in a water-tetrahydrofuranmixture, aqueous hydrochloric acid is preferred. Purification andseparation of the stereoisomers (i.e., enantiomers or diastereomers) canbe achieved by methods known in the art, for example, conversion to achiral salt and crystallization, chiral chromatography, or chiral HPLC.

5.4. PREPARATION OF ENANTIOMERICALLY PURE (R)-DIDESMETHYLSIBUTRAMINE

Enantiomerically pure (R)-didesmethylsibutramine can be prepared asshown below in Schemes 6.

wherein each of R₇, R₈, R₉, R₁₀, and R₁₁ are defined above.

5.5. PREPARATION OF ENANTIOMERICALLY PURE (S)-DIDESMETHYLSIBUTRAMINE

Enantiomerically pure (S)-didesmethylsibutramine can be prepared asshown below in Schemes 7.

wherein each of R₇, R₈, R₉, R₁₀, and R₁₁ are defined above.

5.6. PREPARATION OF(R)-{1-[1-(4-CHLORO-PHENYL)-CYCLOBUTYL]-3-METHYL-BUTYLIDENE}-SULFINAMICACID (1S,2R)-1-PHENYL-2-(4-METHYLPHENYL SULFONYLAMINO)-PROPYL ESTER

To a 100 mL three-necked flask equipped with a magnetic stir bar, anargon inlet, a thermometer probe and rubber septum, was charged1-(4-chloro-phenyl)-cyclobutane-carbonitrile (CCBC) (5.0 g, 25.0 mmol,96%), toluene (20 mL) and isobutyl magnesium chloride (20 mL, 0.9 M inMTBE). The reaction mixture was distilled to the internal temperatureof >100° C. and the resulting mixture refluxed for 2 h. After cooling toroom temperature, the mixture (8.5 mL) was added slowly to a solution of(2S, 4R, 5s)-(4-Methyl-5-phenyl-3-(4-methyl phenylsulfonyl)-[1,2,3]-oxathiazolidine-2-oxide (2.0 g) in THF (14 mL) at −78°C. The mixture was stirred at −78° C. for 4 h, warmed to 10° C. withstirring and the reaction was monitored by TLC. The reaction wasquenched by slow addition of saturated aqueous NaHCO₃ solution (10 mL)and diluted with ethyl acetate (20 mL). The organic phase was washedwith 20% aqueous NaCl solution and dried over Na₂SO₄. After evaporationof the organic solvent to dryness, the residue was purified bychromatography using CH₂Cl₂/EtOAc (9.6:0.4) as a eluate to yield thetitle compound (2.8 g, 80%). ¹H NMR (CDCl₃): δ 0.640 (d, J=6.0 Hz, 6H),1.043 (d, J=6.6 Hz, 3H), 1.660 (b, 1H), 1.835-1.912 (m, 2H), 2.223-2.308(m, 2H), 2.417 (s, 3H), 2.417-2.536 (m, 2H), 2.733-2.885 (m, 2H),3.670-3.748 (m, 1H), 5.5.562 (d, J=2.1 Hz, 1H), 5.905 (d, J=9.0 Hz, 1H),7.125-7.151 (m, 3H), 7.224-7.366 (m, 8H), 7.851 (d, J=8.4 Hz, 2H). ¹³CNMR (CDCl₃): δ 15.19, 15.83, 21.61, 22.44, 22.56, 27.87, 32.67, 42.16,54.27, 56.80, 77.79, 126.10, 127.28, 128.16, 128.45, 128.57, 128.87,129.77, 133.05, 137.65, 138.24, 141.05, 143.41, 188.55. Anal.C₃₁H₃₇ClN₂O₄S₂. Cal: C, 61.93; H, 6.20; N, 4.66; S, 10.67.

Found: C, 61.68; H, 6.12; N, 4.47; S, 10.67.

5.7.(R)-{1-[1-(4-CHLORO-PHENYL)-CYCLOBUTYL]-3-METHYL-BUTYLIDENE}-SULFINAMICACID (1R, 2S)-1-(2,4,6-TRIMETHYL-BENZENESULFONYL AMINO)-INDAN-2-YL ESTER

The captioned compound was prepared using the same procedure asdescribed above. The product was obtained in 75% yield. ¹H NMR (CDCl₃):δ 0.645-0.703 (m, 6H), 1.606 (m, 1H), 1.740-1.915 (m, 2H),2.157-2.257(m, 2H), 2.320 (s, 3H), 814.37 2.715 (s, 6H), 2.832-2.984 (m,2H), 3.179 (dd, J1=4.64 Hz, J2=16.965 Hz, 1H), 3.359 (d, J=16.84 Hz,1H), 4.975 (dd, J1=4.85 Hz, J2=9.27 Hz, 1H), 5.395 (d, J=9.03 Hz, 1H),5.870 (m, 1H), 6.838 (d, J=7.45 Hz, 1H), 6.992 (s, 2H), 7.08-7.15 (m,1H), 7.18-7.23 (m, 2H), 7.308-7.405 (m, 4H). ¹³C NMR (CDCl₃): δ15.891,21.143, 22.625, 23.328, 27.633, 31.995, 32.865, 39.093, 42.406, 56.953,60.417, 76.335, 124.126, 125.271, 127.436, 128.702, 128.941, 132.215,132.991, 135.185, 138.960, 139.126, 140.133, 141.675, 142.440, 187.856.Anal: C₃₃H₃₉ClN₂O₄S₂. Cal: C, 63.19; H, 6.27; N, 4.47; S, 10.22 . Found:C, 63.17; H, 6.21; N, 4.32; S, 9.86.

5.8. PREPARATION OF STEREOMERICALLY PURE IMINE PRECURSORS OF (R)— and(S)-DIDESMETHYLSIBUTRAMINE

Stereomerically pure imine precursors of (R)— and(S)-didesmethylsibutramine can prepared as described in Scheme 8.

5.8.1. PREPARATION OF (2S, 4R)-5,5-DIMETHYL-4-PHENYL-3-(4-METHYLPHENYL-SULFONYL)-[1,2,3]-OXATHIAZOLIDINE-2-OXIDE

To a solution of(1R)—N-(2-hydroxy-2-methyl-1-phenyl-propyl)-4-methyl-benzene sulfonamide(2.0 g, 6.3 mmol) in THF 8 mL at −45° C. was added SOCl₂ (1.12 g, 9.4mmol), followed by slow addition of pyridine (1.24 g, 12.9 mmol) in THF(8 mL) over a period of 2 h. The reaction was monitored on TLC. Thereaction was quenched by addition of saturated aqueous NaHCO₃ and themixture was extracted with EtOAc (30 ml), and organic phase washed withbrine (20 mL) and evaporated to dryness. The residue was added hexane(40 mL) and stirred at ambient for 2 h. The precipitate formed wasfiltered and wet cake washed with hexane to afford the title compound(2.0 g, 87.5%) with 99% de.

5.8.2. PREPARATION OF(R)-{1-[1-(4-CHLORO-PHENYL)-CYCLOBUTYL]-3-METHYL-BUTYLIDENE}-SULFIN-AMICACID (R)-1,1-DIMETHYL-2-PHENYL-2-(4-METHYLPHENYL-SULFONYLAMINO)-ETHYLESTER

The captioned compound was prepared using the same procedure as Scheme 8for the preparation of the imine above. The product was obtained in 60%yield. ¹H NMR (CDCl₃): δ 0.586 (d, J=6.4 Hz, 3H), 0.637 (d, J=6.4 Hz,3H), 1.174 (s, 3H), 1.644 (m, 1H), 1.802 (s, 3H), 1.78-1.85 (m, 2H),2.08-2.20 9m, 2H), 2.280 (s, 3H), 2.32-2.39 (m, 1H), 2.40-2.50 (m, H),2.74-2.88 (m, 2H), 4.209 (d, J =9.52, 1H), 6.034 (d, J=9.52, 2H0,6.94-7.14 (m, 7H), 7.22-7.26 (m, 4H), 7.36-7.42 (m, 2H). ¹³C NMR(CDCl₃): δ 15.924, 21.552, 22.701, 26.861, 26.982, 27.557, 32.056,33.032, 42.593, 56.694, 66.074, 77.339, 85.431, 126.987, 127.635,127.885, 128.428, 128.913, 129.095, 129.176, 133.040, 136.799, 137.876,141.704, 142.727, 186.751. Analytical data: C₃₂H₃₉ClN₂O₄S₂. Anal: Cal:C, 62.47; H, 6.39; N, 4.55; S, 10.42. Found: C, 62.47; H, 6.25; H, 4.39;S, 10.12.

5.9. PREPARATION OF (2S, 4R)-5,5-DIETHYL-4-PHENYL-3-(4-METHYLPHENYLSULFONYL)-[1,2,3]-OXATHIAZOLIDINE-2-OXIDE

The oxathiazolidine 2-oxide was prepared from(1R)—N-(2-ethyl-2-hydroxy-1-phenyl-butyl)-4-methyl-benzenesulfonamide byfollowing the same procedure in scheme 2, which afforded the productwith 88% yield and 99% de. ¹H NMR (CDCl₃): δ0.739 (t, J=7.40 Hz, 3H),0.968 (t, J=7.42 Hz, 3H), 1.153 (h, J=7.33 Hz, 1H), 1.588 (h, J=7.30 Hz,1H), 1.860 (dh, J1=3.05, J2=7.30 hz, 2H), 2.310 (s, 3H), 4.806 (s, 3H),6.98-7.22 (m, 7H), 7.40-7.46 (m, 2H). ¹³C NMR (CDCl₃): δ7.890, 8.344,21.692, 28.644, 29.858, 68.610, 103.509, 127.779, 128.078, 128.350,129.110, 129.418, 133.420, 135.900, 144.365. Anal: C₁₉H₂₃NO₄S; Cal: C,57.99; H, 5.89; N, 3.56; S, 16.30. Found: C, 58.10; H, 5.73; N, 3.43, S,16.28.

5.10. PREPARATION OF(R)-{1-[1-(4-CHLORO-PHENYL)-CYCLOBUTYL]-3-METHYL-BUTYLIDENE}-SULFINAMICACID (1R)-2-ETHYL-1-[PHENYL-(4-METHYL PHENYLSULFONYLAMINO)-METHYL]-PROPYL ESTER

The captioned compound was prepared using the same procedure as Scheme 8for the preparation of the imine above. The compound was afforded in 90%yield. ¹H NMR (CDCl₃): δ 0.62-0.78 (m, 9H), 1.07 (t, J=7.32 Hz, 3H),1.14-1.1.28 (m 1H), 1.33-1.47 (m, 1H),1.72 (b, 1H), 1.78-1.90 (m, 2H),2.02-2.16 (m, 2H), 2.18-2.24 (m, 1H), 2.25 (s, 3H), 2.30-2.60 (m, 3H),2.74-2.86 (m, 2H), 4.42 (d, J=10.5 Hz, 1H), 6.49 (d, J=10.26 Hz, 1H),6.87-6.93 (m, 2H), 6.98-7.12 (m, 4H), 7.14-7.20 (m, 2H), 7.24 (s, 3H),7.30-7.36 (m, 2H). ¹³ C NMR (CDCl₃): δ 7.692, 8.849, 15.910, 21.518,22.736, 25.669, 27.660, 27.923, 31.957, 33.054, 42.676, 56.814, 61.568,92.458, 126.880, 127.337, 127.786, 128.434, 128.887, 129.021, 129.708,133.047, 136.506, 138.210, 141.754, 142.369, 187.15. Anal:C₃₄H₄₃ClN₂O₄S₂; Cal: C, 63.48; H, 6.74; N, 4.35; S, 9.97. Found: C,63.10; H, 6.76; N, 4.04, S, 9.95.

5.11. (R)-{1-[1-(4-CHLORO-PHENYL)-CYCLOBUTYL]-PENTYLIDENE}-SULFINAMICACID (1S, 2R)-1-PHENYL-2-(4-METHYL PHENYL SULFONYLAMINO)-PROPYL ESTER

The captioned compound was prepared using the same procedure as Scheme 8for the preparation of the imine above except that n-butyl magnesiumchloride was used. The compound was afforded 60% yield. ¹H NMR (CDCl₃):δ 0.680 (t, J=6.59 Hz, 3H), 0.949-1.150 (m, 6H), 1.700 (s, 1H),1.857-1.951 (m, 2H), 2.180-2.358 (m, 2H), 2.432 (s, 3H), 2.430-2.544 (m,2H), 2.720-2.920 (m, 2H), 3.660-3.770 (m, 1H), 5.574 (d, J=2.19 Hz, 1H),5.886 (d, J=9.28 Hz, 1H), 7.099-7.130 (m, 2H), 7.256-7.362 (m, 9H),7.851 (d, J=8.30 Hz, 2H). ¹³C NMR (CDCl₃): δ13.513, 15.431, 15.921,21.828, 23.196, 31.604, 32.041, 32.199, 33.312, 54.393, 56.780, 77.736,126.268, 127.518, 128.388, 128.615, 128.684, 129.137, 129.982, 133.385,137.869, 138.464, 141.142, 143.643, 189.997. Anal: C₃₁H₃₇ClN₂O₄S₂; Cal:C, 61.93; H, 6.20; N, 4.66; S, 10.67. Found: C, 61.97, H, 6.12; N, 4.61;S, 10.30.

5.12. ASYMMETRIC SYNTHESIS OF (R)-DDMS VIA REDUCTION OF IMINE

(R)-Didesmethylsibutramine can be prepared by reduction of the imine asdescribed in Scheme 9.

5.12.a. REDUCTION WITH NABH₄ IN THE PRESENCE OF TITANIUM LEWIS ACID

To a two necked round bottomed flask contained a magnetic stirring bar,and temperature probe and an argon outlet was charged the imine (0.1 g,0.167 mmol, 1.0 eq), THF (3 mL) and Ti(OEt)₄ (0.076 g, 2.0 eq), and themixture was stirred at ambient temperature for 1 h. The mixture was thencooled to −45° C. and NaBH₄ (0.025 g, 4.0 eq) was added. After stirredfor 3 h, the reaction mixture was warmed slowly up to −10° C.-−15° C.and the reaction monitored on TLC. HCl/MeOH (4.0 mL, 4M) was addedslowly to quench the reaction and the resulting mixture was stirred atr.t for 3 h. The mixture was cooled to 0° C. and NaOH (5.0 M) was addedto a pH>11 and diluted with EtOAc (20 mL). The organic phase was washedwith brine (5 mL) and evaporated to dryness. The residue was analyzed onHPLC for yield and ee.

5.13. THE RESULTS FOR THE REDUCTION OF IMINES USING PHENYLOXATHIAZOLIDINE CHIRAL AUXILIARY

Stereomerically pure imines derived from a phenyl-oxathiazolidine chiralauxiliary can be reduced to stereomerically pure didesmethylsibutramneby the reaction conditions described below.

To a two necked round bottomed flask contained a magnetic stirring bar,and temperature probe and an argon outlet was charged the imine (1.0eq), the solvent and the mixture was cooled to the reaction temperature.Then reducing reagent was added under stirring. The reaction wasmonitored on TLC and worked up by following the above procedure. Yield(HPLC Entry Reducing reagents and reaction condition (R)/(S) analysis) 1NaBH₄/THF/−45° C.-0° C. 80:20 97% 2 NaBH₄/MeOH/−45° C.-−20° C. 72:28 95%3 NaBH₄CH₃CN/H₂O/0° C. 66:34 98% 4 NaBH₄/THF/MgBr₂.OEt₂ (No reaction) 5NaBH₄/THF/MgBr₂.OEt₂/MeOH)/−45° C.-0° C. 64.5:35.5 65% (No reactionwithout MeOH) 6 NaBH₄/Ti(OPr)₄/THF/−45° C.-−20° C. 85.8:14/8 80% 7NaBH₄/THF/Ti(O^(i)Pr)₄/−45° C.-−30° C. 88:12 95% 8NaBH₄/THF/Ti(OEt)₄/−45° C.-−30° C. 85:15 95% 9 NaBH₄/THF/BF₃ −45° C.-0°C. 64:36 75% 10 NaBH₄/THF/Zr(OBu-t)₄/−45° C.-0° C. 80:20 95% 11NaBH₄/THF/Zr(OEt)₄/−45° C.-10° C. 82:18 95% 12 NaBH₄/THF/TiCl₄/−45° C.60:40 70% 13 NaBH₄/THF/ZnCl₂/−45° C.-r.t 77:33 95% 14 LiBH₄/THF/−78°C.-−30° C. 51:49 95% 15 BH₃/THF/−78° C.-−10° C. 32:68 75% (isolated) 169-BBN/THF/0° C. 84:16 80% 17 Catecholborane 49:51 96% 18 L-Selectride43:57 <5% 19 K-Selectride 46:54 <5% 20 DIBAL/THF/−45° C.-−30° C. 76:2470% 21 DIBAL/THF/ZnCl₂/−45° C.-−0° C. 79:21 75% 22NaBH₄/Ti(OPr)₃Cl/THF/−45° C.-r.t 68:32  5% 23 NaBH(OMe)₃/THF//−45°C.-−15° C. 71:29 96% 24 Red-Al/THF/−45° C. 75:25 85% 25 Na(OAc)₃BH/THF(No reaction) 26 NaBH₃CN/THF/r.t (No reaction with MeOH, or AcOH, orTi(OEt)₄ 27 Me₄NBH(OAc)₃/THF/r.t (No reaction with MeOH, or AcOH, orTi(OEt)₄

5.13.a. SOLVENT EFFECT ON THE STEREOSELECTIVITY

Reducing reagents and reaction Yield (HPLC Entry condition (R)/(S)analysis) 1 NaBH₄/Ti(OEt)₄/THF/r.t 82:18 93% 2 NaBH₄/Ti(OEt)₄/MeOH/r.t60:40 75% 3 NaBH₄/Ti(OEt)₄/EtOH/r.t 72.5:27.5 95% 4NaBH₄/Ti(OEt)₄/MTBE/r.t 83:17 78%

5.14. SYNTHESIS OF 1-[1-(4-CHLORO-PHENYL)-CYCLOBUTYL]-PENTYLAMINE

Stereomerically pure 1-[1-(4-chloro-phenyl)-cyclobutyl]-pentylamine canbe obtained from a phenyl-oxathiazolidine chiral auxiliary by thereaction conditions described below.

Reducing reagents and reaction Yield (HPLC Entry condition (R)/(S)analysis) 1 NaBH₄/Ti(OPr^(i))₄/THF/−45° C. 88:12 85%

5.15. SYNTHESIS OF (R)-DIDESMETHYLSIBUTRAMINE USING INDAN-2-YL CHIRALAUXILIARY

Stereomerically pure didesmethylsibutramine can be obtained from astereomerically pure indan-2yl-sulfinyl chiral auxiliary by the reactionconditions described below.

Yield Reducing reagents and reaction (HPLC Entry condition (R)/(S)analysis) 1 NaBH₄/THF/Ti(OiPr)₄/−45° C.-−10° C. 79:21 87% 2NaBH₄/THF/Ti(OEt)₄/−45° C.-−10° C. 83.3:16.7 95% 3 NaBH(Oac)3/THF Noreaction

5.16. SYNTHESIS OF (R)-DIDESMETHYLSIBUTRAMINE USING DIMETHYLOXATHIAZOLINDINE CHIRAL AUXILIARY

Stereomerically pure didesmethylsibutramine can be obtained from astereomerically pure dimethyl-sulfinyl chiral auxiliary by the reactionconditions described below.

Reducing reagents and Yield (HPLC Entry reaction condition (R)/(S)analysis) 1 NaBH₄/THF//−20° C.-−5° C. 89:11 90% 2NaBH₄/THF/Ti(O^(i)Pr)₄/−45° C.-−5° C. 94:6  80% 3NaBH₄/THF/Ti(OPr)₄/−45° C.-−10° C. 94.2:5.8  80% 4NaBH₄/THF/Ti(OEt)₄/−15° C. 95:5  95%

5.17. SYNTHESIS OF (R)-DIDESMETHYLSIBUTRAMINE USING DIETHYLOXATHIAZOLINDINE CHIRAL AUXILIARY

Stereomerically pure didesmethylsibutramine can be obtained from astereomerically pure diethyl-sulfinyl chiral auxiliary by the reactionconditions described below.

Reducing reagents and Yield (HPLC Entry reaction condition (R)/(S)analysis) 1 NaBH₄/THF/Ti(OEt)₄/−15° C. 87:13 95% 2NaBH₄/THF/Ti(O^(i)Pr)₄/−45° C.-−15° C. 88:12 90%

5.18. ONE POT PROCEDURE FOR THE ASYMMETRIC SYNTHESIS OF (R)-DDMS-D-TA

The one-pot asymmetric synthesis of stereomerically pure D-tartaric acidsalt of (R)-didesmethylsibutramine is described below.

To a 100 mL three-necked flask equipped with a magnetic stir bar, anargon inlet, a thermometer probe and rubber septum, was charged1-(4-chloro-phenyl)-cyclobutanecarbonitrile (CCBC) (8.0 g, 41.9 mmol(96%)) and CuBr (0.12 g, 2%). After purging the flask with argon for 10min, MTBE (15 mL) and iBuMgCl (68 mL, 0.61 mol in MTBE) were added andthe reaction mixture was refluxed for 4-6 h. The reaction was monitoredon HPLC for the disappearance of CCBC. The reaction mixture was cooledto ambient temperature and added drop-wise to the solution of(2S,4R,5S)-4-methyl-5-phenyl-3-(4-methylphenyl-sulfonyl)-[1,2,3]-oxathiazolidine-2-oxide (15.0 g, 42 mmol) inTHF (100 mL) in a 500 mL round-bottomed flask at −78° C. The reactionmixture was stirred for 4 h and warmed up to 10° C. under stirring. Thereaction was monitored on TLC for the disappearance of1-[1-(4-chloro-phenyl)-cyclobutyl]-3-methyl-butylideneamine. Then thereaction mixture was cooled to 0° C. and aqueous ammonium acetate (30%,50 mL) was added, follows by MTBE (200 mL) and warmed up to ambienttemperature. The organic phase was washed with 30% KHCO₃ (50 mL) and 20%NaCl (50 mL) and polish filtered through two layers of filter paper.After the resulting organic phase was distilled under reduced pressureto about 50 mL (KF=0.58%), anhydrous THF (80 mL) and Ti(OPr^(i))₄ wereadded and the mixture was stirred at ambient temperature for 1 h andcooled to −45° C. NaBH₄ (6.4 g, 168 mmol) was added in one portion andthe mixture was stirred for 6 h and warmed up to −20° C. and thereaction was monitored on TLC for the disappearance of startingmaterial. To the reaction mixture was slowly added aqueous HCl dissolvedin MeOH (60 mL, 4M) and the mixture was warmed to ambient temperatureand stirred for 3h. After the mixture was cooled to 0° C., NaOH (5 M)was added slowly to pH ˜12 for the solution, the mixture was dilutedwith toluene (200 mL), and was distilled under reduced pressure toremove the low boiling point solvents. The organic phases were allowedto separate for 20 min and the organic phase was washed twice withaqueous NaCl (50 mL, 20%). The mixture was heated to 60-70° C. andD-tartaric acid (6.3 g) in water (13 ml) and acetone (6 mL) was addedslowly. The mixture was distilled under azeotropic condition until theinternal temperature reached >95° C. The mixture was then cooled toambient temperature and stirred for 1 h. The slurry formed was filteredand the wet cake was washed with toluene (30 mL×2) and MTBE (30 mL) anddried at 45° C. for 24 h under reduced pressure to afford the(R)-DDMS.D-TA with 85% yield and 70% ee.

5.18.a. RECOVERY OF (1S,2R)-NOREPHEDRINE N-TOSYLATE

The above mother liquor was vacuum distilled to about 60 mL and water(50 mL) was added. The resulting mixture was distilled until all theinternal temperature reached to ˜100° C. and mixture was stirred.Heptane (40 mL) was added and the mixture was stirred to ambienttemperature while a nice slurry was formed. The slurry was filtered andthe wet cake was washed with water (20 mL) and heptane (30 mL) and driedat 45° C. under reduced pressure to afford 12.5 g (1S,2R)-norephedrineN-tosylate (89.5%).

5.19 PREPARATION OF SULFOXIDE AND SULFONYLAMINE STEREOISOMERS

Tert-Butylsulfonylquinine (TBSOQ) was isolated in 92% yield, and greatthan 99% d.e. when (−)-Quinine was used as the chiral auxiliary, andtert-butylmagnesium chloride was used as the first nucleophile (R¹M).Displacement of the auxiliary with a second nucleophile (R²M)such asalkyl Grignard reagent, or Aryl diethylaluminium provided theenantiomeric enriched sulfoxides. When TBSOQ was treated with amideanions such as lithium amide in liquid ammonia or lithiumbis(trimethylsily)amide in solvent such as TB:F, afforded theenantiomeric enriched sulfinylamides.

TABLE 1 Preparation of TBSOQ Temp · Yield d.e. Entry Ligand R₁M Solvent(□ C) Product (%) (%) 1 (−)- t- THF −78 (R)- 92 >99 Quinine BuMgCl 2

t- BuMgCl THF −78 15

TABLE Nucleophilic dispacement of TBSOQ to form sulfoxide orsulfinylamine Yield E.e. Entry Base R₁M R₂M Product (%) (%) Et₃Nt-BuMgCl PhMgCl

93 >99 Et₃N t-BuMgCl ^(i)PrMgCl

91 >99 Et₃N t-BuMgCl sec- BuMgCl

95 >99 Et₃N t-BuMgCl

81 >99 Et₃N p-Tolyl₂Cu p-TolylAlEt₂ MeMgCl

88 >99 Et₃N t-BuMgCl LiHMDS

70 96

Novel Practical Process for Preparation of Enantiopure Sulfinylamines

Supporting Information

General. Unless otherwise noted, all reagents were obtained fromcommercial suppliers and were used without further purification. Allanhydrous solvents were used for the reaction, and were purchased fromAldrich. All reactions, unless otherwise noted, were carried out in ovendried glassware under inert argon atmosphere. Chromatography was carriedout using Silicycle 60, 230-400 mesh silica gel. Thin-layerchromatography (TLC) analysis was performed with Merk Kieselgel 60 F 254plates, and was visualized using UV light and/or phosphomolybdicstaining. ¹H NMR and proton-decoupled ¹³C NMR spectra were obtained witha Varian Inova 300 spectrometer in CDCl₃ with TMS as an internalstandard at room temperature. Proton and carbon spectra chemical shiftswere reported using TMS and/or CDCl₃ as an internal standard at 0 ppmand at 77.23 ppm, respectively. Diastereomeric ratios were determined on¹H NMR spectrum analyses. Elemental analyses were performed byQuantitative Technologies, Inc., Whitehouse, N.J. Enantiomeric excesseswere obtained by chiral HPLC analysis using Chiralpak A S, Chiralcel OB, or Chiralcel O D column.Preparation of TBSOQ:

A 4-neck 1 L round-bottom flask fitted with a mechanical stirrer,addition funnel, temperature probe, and argon inlet was charged with(−)-quinine (3.0 g, 9.25 mmol, 1.0 equiv.) and THF (80 mL). The solutionwas chilled to −60° C., thionyl chloride (0.75 mL, 10.28 mmol, 1.1equiv.) was added dropwise via a syringe. The mixture was stirred for 10min, followed by addition of Et₃N (2.9 mL, 20.85 mmol, 2.2 equiv.) overa 5 min period. The resultant mixture was stirred at between −37˜−45° C.for 1 hr, followed by addition of tert-butyl magnesium chloride (19 mL,1.0 M in THF, 19.0 mmol, 2.05 equiv.) at −78° C. The resultant clearreaction was stirred at −75° C. for 2 h and monitored by TLC analysis.Once the reaction was completed, the reaction was quenched withsaturated NaHCO₃ aqueous solution (90 mL), and the mixture was dilutedwith ethyl acetate (150 mL) and warmed to ambient temperature withstirring. The phases were allowed to separate and the aqueous phase wasremoved. The aqueous phase was extracted with ethyl acetate (100 mL).The combined organic phases were washed with brine (60 mL), dried, andevaporated to give diastereopure TBSOQ. The yellowish oily product waspurified by flash column chromatography (eluent with 5% MeOH in AcOEt)to remove impurities derived from the starting material, and give pureTBSOQ as colorless oil which turned into white solid after standing atambient temperature (3.6 g, 91% yield). The diastereomeric excessis >99% as determined by ¹H NMR spectrum and HPLC.

¹H NMR (CDCl₃) δ

¹³C NMR (CDCl₃) δ

HPLC method: Symmetry C-18, 4.6 mm×150 mm, 5 μ; 222 nm; 0.5 mL/min.;MeOH/H₂O 80:20.

(S)-tert-Butyl phenylsulfoxide

A solution of TBSOQ (1.79 g, 4.14 mmol, 1.0 equiv.) in THF (20 mL) at−78° C. under argon was charged dropwise with phenylmagnesium bromide(2.8 mL, 3.0 M in Et₂O, 8.3 mmol, 2.0 equiv.). After being stirred at−78° C. for 1 h, the reaction mixture was warmed to 22° C., and thereaction was monitored by TLC analysis. The reaction was quenched by 20%NaCl (15 mL) aqueous solution and diluted with EtOAc (30 mL). Afterphase separation, the organic phase was extracted once with EtOAc. Thecombined organic phases was washed with 20% NaCl (10 mL) aqueoussolution, dried over Na₂SO₄, and concentrated to give the mixture of(S)-tert-Butyl phenylsulfoxide and (−)-quinine, which was purified byflash chromatography eluted with EtOAc to afford (S)-t-butylisobutyllsulfoxide (0.76 g, 93%) in >99% ee. The enantiomeric purity wasanalyzed by chiral HPLC analysis. The configuration at sulfur atom wasdeduced by comparison of the optical rotation with that of reported inliterature.

¹H NMR (300 MHz, CDCl₃): δ 1.20 (s, 9H), 7.53 (m, 3H), 7.63 (m, 3H). ¹³CNMR (75 MHz, CDCl₃): δ23.0, 56.0, 126.6, 128.6, 131.4, 140.2. [α]²²_(D)=−184 (c, 0.84, CHCl₃); Lit.²+175.

(R)-tert-Butyl (tert-butylsulfinyl)acetate (R₂═LiCH₂COOBu-t)

A solution of diisopropylamine (0.3 mL, 2.14 mmol) in THF (4 mL) at −15°C. was added n-BuLi (1.3 mL, 1.6 M in hexane, 2.08 mmol) slowly. Themixture was warmed to 0° C., stirred for 30 min and cooled to −45° C.,followed by addition of tert-butyl acetate (0.28 mL 2.08 mmol, 1.0 eq).The reaction mixture was stirred for 30min and was cooled to −78° C. Asolution of TBSOQ (300 mg, 0.70 mmol) in THF (2 mL) was added slowlywhile keeping the reaction mixture at −78° C.˜−75° C. and the reactionwas monitored by TLC analysis. The reaction was worked up and the crudeproduct was purified by flash chromatography eluted with EtOAc-MeOH(5:1) to afforded the title compound (133 mg) in a 81% yield and >99%ee. ¹H NMR (CDCl₃): δ 1.28 (s, 9H), 1.51 (s, 9H), 3.29 (d, 1H), 3.47 (d,1H). ¹³C NMR (CDCl₃): δ 22.7, 27.9,52.8, 54.0, 83.1, 1654.

Chiral BPLC method: Chiralpak AS 4.6 mm×250 mm, 10 μ; 222 nm; 0.8mL/min.; Hex/EtOH 90:10; (S)-isomer, t_(R)=11.2 min; (R)-isomert_(R)=13.2 min. (99.8% ee).

p-Tolylmagnesium bromide (15 mL, 1.0 M in THF, 15 mmol, 2.1 equiv.) wasadded to a solution of diethylaluminium chloride (8.3 mL, 1.8 M intoluene, 15 mmol, 2.1 equiv.) at −60° C. to −50° C. The mixture was thencooled to −78° C. and stirred for 0.5 hr. In another 3-neck 250 mLround-bottom flask fitted with addition funnel, temperature probe, andargon inlet was charged with (−)-quinine (2.27 g, 7.0 mmol, 1.0 equiv.)and TBF (48 mL). The solution was chilled to −75° C., thionyl chloride(0.54 mL, 7.40 mmol, 1.05 equiv.) was added dropwise via a syringe. Themixture was stirred for 10 min, followed by addition of Et₃N (2.14 mL,15.4 mmol, 2.2 equiv.) over a 5 min period. The resultant mixture wasstirred for 30 min, followed by addition of the above-mentioned p-tolyldiethylaluminium at the same temperature. The resultant clear reactionwas stirred at −75° C. for 2 h and monitored by TLC analysis. Thereaction was then quenched with saturated aqueous solution of Rochelle'ssalt and extracted with ethyl acetate (2×25 mL). The organic extractswere washed with brine and evaporated. The residue was purified by flashchromatography eluted with 5% methanol in EtOAc to affordp-tolylquininyl sulfoxide ester (2.5 g) in 78% yield.

Methyl magnesium chloride (100 uL, 3.0 M in THF, 0.3 mmol, 1.4 equiv)was added to a solution of the p-tolylquininyl sulfoxide ester (100 mg,0.216 mmol) in TBF (2 mL) at −60° C. to −78° C. The reaction mixture wasthen stirred at −78° C. for 30 min and the reaction was monitored by TLCanalysis. The reaction was then quenched with saturated KHCO₃ aqueoussolution and extracted with ethyl acetate (2×10 mL). The organicextracts were washed with brine and evaporated. The residue was purifiedby flash chromatography eluted with EtOAc to afford the title compound(30 mg) in 88% yield. The diastereomeric excess is >99% as determined by“PLC. The absolute configuration is deduced from comparison withauthentic sample.

Chiral BPLC method: Chiralpak AS, 90:10 Hex/EtOH, 1 min/mL

The present invention is not to be limited in scope by the specificembodiments disclosed in the examples which are intended asillustrations of a few aspects of the invention and any embodimentswhich are functionally equivalent are within the scope of thisinvention. Indeed, various modifications of the invention in addition tothose shown and described herein will become apparent to those skilledin the art and are intended to fall within the appended claims.

1. A method of preparing an amine stereoisomer, which comprisesstereoselectively reducing a sulfinylimine that bears on the sulfinylgroup a residue of an alcohol, thiol or amine, or reacting asulfinylimine stereoisomer that bears on the sulfinyl group a residue ofan alcohol, thiol or amine with a source of a nucleophile, to afford asulfinylamine stereoisomer, followed by contacting the sulfinylaminestereoisomer with a reagent suitable for the cleavage of asulfur-nitrogen bond, to afford an amine stereoisomer.
 2. A method asclaimed in claim 1, wherein the sulfinylimine is a sulfinyliminestereoisomer.
 3. A method as claimed in claim 1, wherein the residue ofthe alcohol, thiol or amine is in stereoisomeric form.
 4. A method asclaimed in claim 1, wherein the residue of the alcohol, thiol or amineis a residue of an optionally N-substituted beta-amino alcohol, thiol oramine.
 5. A method as claimed in claim 4, wherein the optionallyN-substituted beta-amino alcohol, thiol or amine is a compound of thegeneral formula

wherein A₁ is R₇N or (R_(7′)) R_(7″)N, R₇ represents hydrogen or-L-R_(7a) in which -L- represents a bond, —CO—, —(CO)O—, —(CO)NR_(7b)—,—SO—, —SO₂—, or —(SO₂)O—, each of R_(7a) and R_(7b) independentlyrepresents substituted or unsubstituted alkyl, substituted orunsubstituted aralkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl, and R_(7′) and R_(7″) are as defined for R_(7a), or R_(7′)and R_(7″) together with the nitrogen atom to which they are attachedand, optionally R₈, form an unsubstituted or substituted heterocyclicgroup, or R_(7′) together with the nitrogen atom to which it is attachedand the carbon atom to which the nitrogen atom is attached forms anunsubstituted or substituted heterocyclic group; A₂ is O, S or NR_(7c)in which R_(7c) is substituted or unsubstituted alkyl, substituted orunsubstituted aralkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl; and each of R₈, R₉, R₁₀ and R₁₁ is independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedaralkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl, or R₈ andR₁₁ together form a substituted or unsubstituted alkylene orheteroalkylene chain.
 6. A method as claimed in claim 5, wherein A₂ isO.
 7. A method as claimed in claim 5, wherein each of R₈ R₉, R₁₀ and R₁₁is independently selected from hydrogen, (1-4C)alkyl and phenyl, or thealcohol is selected from (N-methylpyrrolidin-2-yl)diphenylmethanol,quinine, quinidine, hydroquinine, cinchonidine, cinchonine,hydrocinchonidine and ethyl hydrocupreine.
 8. A method as claimed inclaim 7, wherein A₁ is R₇N wherein R₇ represents —SO₂—R_(7a) in whichR7a represents (1-6C)alkyl, (6-10C)aryl(1-4C)alkyl or (6-10C)aryl inwhich any aryl group is unsubstituted or substituted by one, two orthree substituents selected independently from halogen, (1-4C)alkyl and(1-4C)alkoxy, or A_(1′) is (R_(7′))R_(7″)N wherein R_(7′) and R_(7″)each independently represents a (1-4C)alkyl group or together with thenitrogen to which they are attached represent a pyrrolidine group thatmay bear one or two methyl substituents, or the alcohol is selected from(N-methylpyrrolidin-2-yl)diphenylmethanol, quinine, quinidine,hydroquinine, cinchonidine, cinchonine, hydrocinchonidine and ethylhydrocupreine.
 9. A method as claimed in claim 7, wherein A_(1′) is R₇Nand the residue of the alcohol, thiol or amine is a residue of anoptionally N-substituted 2-amino-1-phenylpropanol,2-amino-2-methyl-1-phenylpropanol, 1-amino-1-phenyl-2-propanol,1-amino-1-phenyl-2-methyl-2-propanol,1-amino-1-phenyl-2-ethyl-2-butanol, 1-amino-2-indanol,2-aminoindan-1-ol, 1-amino-2-hydroxy-1,2,3,4-tetrahydronaphthalene or2-amino-1-hydroxy-1,2,3,4-tetrahydronaphthalene, or A_(1′) is(R_(7′))R_(7″)N and the alcohol is selected from2-N,N-dimethylamino-1-phenyl-2-propanol,2-N,N-dibutylamino-1-phenylpropanol, 2-pyrrolidin-1-yl-1-phenylpropanol,2-(2-methylpyrrolidin-1-yl)-1-phenylpropanol,2-(2,5-dimethylpyrrolidin-1-yl)-1-phenylpropanol,2-N,N-dimethylamino-2-methyl-1-phenylpropanol,(N-methylpyrrolidin-2-yl)diphenylmethanol, 1-pyrrolidin-1-ylindan-2-ol,3-benzyloxy-2-N,N-dimethylamino-1-phenylpropan-2-ol, quinine, quinidine,hydroquinine, cinchonidine, cinchonine, hydrocinchonidine and ethylhydrocupreine.
 10. A method as claimed in claim 4, wherein thesulfinylimine has been prepared by contacting an iminometal with a1,2,3-oxathiazolidine-S-oxide, a 1,2,3-dithiazolidine-S-oxide or a1,2,3-azathiazolidine-S-oxide.
 11. A method as claimed claim 10, whereinthe 1,2,3-oxathiazolidine-S-oxide, a-1,2,3-dithiazolidine-S-oxide or1,2,3-azathiazolidine-S-oxide is a compound of formula 3 or 3′

wherein A₁ is R₇N or (R_(7′))R_(7″)N⁺Q⁻ in which Q− is an anion, R₇represents hydrogen or -L-R_(7a) in which -L- represents a bond, —CO—,—(CO)O—, —(CO)NR_(7b)—, —SO—, —SO₂—, or —(SO₂)O—, each of R_(7a) andR_(7b) independently represents substituted or unsubstituted alkyl,substituted or unsubstituted aralkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl, and R_(7′) and R_(7″) are as defined forR_(7a)or R_(7′) and R_(7″) together with the nitrogen atom to which theyare attached and, optionally R₈, form an unsubstituted or substitutedheterocyclic group, or R_(7′) together with the nitrogen atom to whichit is attached and the carbon atom to which the nitrogen atom isattached forms an unsubstituted or substituted heterocyclic group; A₂ isO, S or NR_(7c) in which R_(7c) is substituted or unsubstituted alkyl,substituted or unsubstituted aralkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl; and each of R₈, R₉, R₁₀ and R₁₁ isindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted aralkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl, or R₈ and R₁₁ together form a substituted or unsubstitutedalkylene or heteroalkylene chain; the iminometal is a compound offormula 1′

wherein M is CdZ, BaZ, Na, K, MgZ, ZnZ, Li, MnZ, CuZ, TiZ₃ or In and Zis an anion.
 12. A method as claimed in claim 11, wherein the1,2,3-oxathiazolidine-S-oxide, 1,2,3-dithiazolidine-S-oxide or1,2,3-azathiazolidine-S-oxide is a stereoisomer of formula


13. A method as claimed in claim 11, wherein the amine stereoisomer is acompound of formula 5 or 5′

or a pharmaceutically acceptable salt, solvate, clathrate, hydrate orprodrug thereof, wherein R₅ and R₆ are independently substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aralkyl, substituted or unsubstituted arylor substituted or unsubstituted heteroaryl, or R₅ and R₆ together withthe carbon atom to which they are attached form a substituted orunsubstituted cycloalkyl group, and R₁₂ and R₁₃ together with thenitrogen atom to which they are attached form a heterocycle, or each ofR₁₂ and R₁₃ is independently hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted aralkyl, or substituted orunsubstituted aryl; and the sulfinylimine stereoisomer is a compound offormula 4 or 4′

wherein A_(1′) represents R₇N or (R₇′)R_(7″)N.
 14. A method as claimedin claim 13, wherein A₂ is O.
 15. A method as claimed in claim 14,wherein R₅ and R₆ are independently substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedaralkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl; the 1,2,3-oxathiazolidine-S-oxide is acompound of the formula 3 or 3′

in which R₇ represents hydrogen or -L-R_(7a) in which L is a bond or SO₂and R_(7a) is substituted or unsubstituted alkyl, substituted orunsubstituted aralkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl; Z in the iminometal of formula 1′ is Cl, Br or I; and thesulfinylimine stereoisomer is a compound of formula


16. A method as claimed in claim 13, wherein R₁₂ and R₁₃ are bothhydrogen.
 17. A method as claimed in claim 10, wherein the1,2,3-oxathiazolidine-S-oxide, 1,2,3-dithiazolidine-S-oxide or1,2,3-azathiazolidine-S-oxide has been prepared by reacting anoptionally N-substituted beta-amino alcohol, thiol or amine with athionyl halide.
 18. A method as claimed in claim 1, which furthercomprises the step of alkylating the amine stereoisomer.
 19. A method asclaimed in claim 1, wherein the amine stereoisomer is a compound offormula

or a pharmaceutically acceptable salt, solvate, clathrate, hydrate orprodrug thereof, wherein R₁₄ is substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedaralkyl or substituted or unsubstituted aryl, and R₁₅ and R₁₆ togetherwith the nitrogen to which they are attached form a heterocycle, or eachof R₁₅ and R₁₆ is independently hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted aralkyl or substituted or unsubstituted aryl.
 20. A methodas claimed in claim 19, in which the amine stereoisomer is a compound offormula


21. A method as claimed in claim 19, wherein R₁₅ and R₁₆ are bothhydrogen.
 22. A method as claimed in claim 21 wherein the metal imine isa compound of formula

that has been obtained by contacting a compound of formula

with a compound of formula i-BuMg-X wherein X is a halogen.
 23. A methodas claimed in claim 10, wherein the 1,2,3-oxathiazolidine-S-oxide is acompound of the formula


24. A method as claimed in claim 1, wherein the sulfinylimine is reducedusing a hydride reducing agent.
 25. A method as claimed in claim 24,wherein the hydride reducing agent is NaBH₄.
 26. A method as claimed inclaim 1, in which the reagent suitable for the cleavage of asulfur-nitrogen bond is an acid.
 27. A method as claimed in claim 26wherein the acid is HCl.
 28. A method as claimed in claim 1, in whichreaction of the sulfinylamine stereoisomer with the reagent suitable forthe cleavage of a sulfur-nitrogen bond also affords an optionallyN-substituted beta-aminoalcohol, and this optionally N-substitutedbeta-aminoalcohol is recovered, converted into1,2,3-oxathiazolidine-S-oxide and recycled.
 29. A method as claimed inclaim 1, wherein the stereoselective reduction of the sulfinylimine isperformed using a stereoselective reducing agent.
 30. A method asclaimed in claim 1, in which the amine stereoisomer is selected fromAlacepril, Benazepril, Benazeprilate, Ceronapril, Cilazapril,Cilazaprilat, Delapril, Enalapril, Enalaprilat, Fasidotril, Fosinopril,Imidapril, Imidaprilat, Libenzapril, Lisinopril, Moexipril, Moexiprilat,Moveltipril, Pentopril, Perindopril, Quinapril, Quinaprilat, Ramipril,Sampatrilat, Spirapril, Spiraprilat, Temocapril, Temocaprilate,Trandolapril, Trandolaprilate, Utibapril, Utibaprilat, Zabicipril,Zabiciprilat, Bucillamine, Penicillamine, Thiamphenicol, Cefprozil,Cephalexin, Cephaloglycin, Cilastatin, Alafosfalin, Ethambutol,Sertraline, Tametraline, Acetylcysteine, Selegiline, Azaserine,Dorzolamide, Colchicine, Dilevalol, Enalapril, Methyldopa, Metaraminol,Acivicin, Melphalan, Ubenimex, Tmsulosin, Tirofiban, Dilevalol,N-dodecyl-N-methylephedrinium, Ofenucine, Tinofedrine, Aceglutamide,1-ephedrine, levopropylhexedrine, (+)-and (−)-Norephedrine,Phenylpropanolamine, Pseudoephedrine, d-farm, (R)— and (S)-Tamsulosin,Dimepheptanol, Lofentanil, Tilidine hydrochloride (+)-trans, Ciramadol,Enadoline, Lefetamine, Spiradoline, (+)-Etoxadrol, Levoxadrol,(R)-Amphetamine, Clobenzorex, Dexfenfluramine, Dextroamphetamine,Etilamfetamine, Fenfluramine, Levofenfluramine, Phenylpropanolamine,Cetirizine, (R)— and (S)-Baclofen, (R)— and (S)-Sibutramine, andpharmaceutically acceptable salts thereof.
 31. A method as claimed inclaim 1, wherein the sulfinylamine stereoisomer is reacted with a sourceof a nucleophile selected from a nitrile, a Grignard reagent and anorganolithium.
 32. A method as claimed in claim 31, wherein thesulfinylamine stereoisomer is reacted with a nitrile, and the resultantamine stereoisomer bearing a nitrile group is hydrolyzed to afford anamino acid.
 33. A compound of formula

wherein: R₅ and R₆ are independently substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedaralkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl, or R₅ and R₆ together with the carbon atom towhich they are attached form a substituted or unsubstituted cycloalkylgroup; A₁ is R₇N or (R_(7′))R_(7″)N; R₇ represents hydrogen or -L-R_(7a)in which -L- represents a bond, —CO—, —(CO)O—, —(CO)NR_(7b)—, —SO—,—SO₂—, or —(SO₂)O—, each of R_(7a) and R_(7b) independently representssubstituted or unsubstituted alkyl, substituted or unsubstitutedaralkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl, andR_(7′) and R_(7″) are as defined for R_(7a), or R_(7′) and R_(7″)together with the nitrogen atom to which they are attached and,optionally R₈, form an unsubstituted or substituted heterocyclic group,or R_(7′) together with the nitrogen atom to which it is attached andthe carbon atom to which the nitrogen atom is attached forms anunsubstituted or substituted heterocyclic group; A₂ is O, S or NR_(7c)in which R_(7c) is substituted or unsubstituted alkyl, substituted orunsubstituted aralkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl; and each of R₈, R₉, R₁₀ and R₁₁ is independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedaralkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl, or R₈ andR₁₁ together form a substituted or unsubstituted alkylene orheteroalkylene chain; A₂ is O, S or NR_(7c) in which R_(7c) issubstituted or unsubstituted alkyl, substituted or unsubstitutedaralkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl; and eachof R₈, R₉, R₁₀ and R₁₁ is independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted aralkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted aryl orsubstituted or unsubstituted heteroaryl, or R₈ and R₁₁ together form asubstituted or unsubstituted alkylene or heteroalkylene chain, or a saltthereof.
 34. A compound as claimed in claim 33, which is a stereoisomerof formula


35. A compound as claimed in claim 34, wherein A₂ is O.
 36. A compoundas claimed in claim 33, wherein A₁ represents R₇N and R₇ representsR_(7a)SO₂ in which R_(7a) represents a (1-6C)alkyl,(6-10C)aryl(1-6C)alkyl or (6-10C) aryl group, in which the aryl group isunsubstituted or substituted by one, two or three substituents selectedindependently from a halogen atom, a (1-4C)alkyl group and a(1-4C)alkoxy group, or A₁ represents (R_(7′))R_(7″)N in which R_(7′) andR_(7″) each independently represents a (1-4C)alkyl group or togetherwith the nitrogen to which they are attached represent a pyrrolidinegroup that may bear one or two methyl substituents, and each of R₈, R₉,R₁₀ and R₁₁ is independently selected from hydrogen, (1-4C)alkyl andphenyl, or the group

is selected from a residue of (N-methylpyrrolidin-2-yl)diphenylmethanol,1-pyrrolidin-1-ylindan-2-ol,3-benzyloxy-2-N,N-dimethylamino-1-phenylpropan-2-ol, quinine, quinidine,hydroquinine, cinchonidine, cinchonine, hydrocinchonidine and ethylhydrocupreine.
 37. A compound as claimed in claim 32, which is of theformula


38. A compound as claimed in claim 32, wherein A_(1′) representsR_(7a)SO₂N in which R_(7a) represents a (1-6C)alkyl,(6-10C)aryl(1-6C)alkyl or (6-10C) aryl group, in which the aryl group isunsubstituted or substituted by one, two or three substituents selectedindependently from a halogen atom, a (1-4C)alkyl group and a(1-4C)alkoxy group; or the group

is a residue of 2-N,N-dimethylamino-1-phenylpropanol,2-N,N-dibutylamino-1-phenylpropanol, 2-pyrrolidin-1-yl-1-phenylpropanol,2-(2-methylpyrrolidin-1-yl)-1-phenylpropanol,2-(2,5-dimethylpyrrolidin-1-yl)-1-phenylpropanol,2-N,N-dimethylamino-2-methyl-1-phenylpropanol,(N-methylpyrrolidin-2-yl)diphenylmethanol, 1-pyrrolidin-1-ylindan-2-ol,3-benzyloxy-2-N,N-dimethylamino-1-phenylpropan-2-ol, quinine, quinidine,hydroquinine, cinchonidine, cinchonine, hydrocinchonidine or ethylhydrocupreine.
 39. A compound of formula

wherein A₁ is (R₇)R_(7′)N⁺Q⁻ in which Q− is an anion and each of R₇ andR_(7′) independently represents substituted or unsubstituted alkyl,substituted or unsubstituted aralkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl, or two substituents R₇ together with thenitrogen atom to which they are attached and, optionally R₈, form anunsubstituted or substituted heterocyclic group, or one R₇ substituenttogether with the nitrogen atom to which it is attached and the carbonatom to which the nitrogen atom is attached form an unsubstituted orsubstituted heterocyclic group; A₂ is O, S or NR_(7c) in which R_(7c) issubstituted or unsubstituted alkyl, substituted or unsubstitutedaralkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl; and eachof R₈, R₉, R₁₀ and R₁₁ is independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted aralkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted aryl orsubstituted or unsubstituted heteroaryl, or R₈ and R₁₁ together form asubstituted or unsubstituted alkylene or heteroalkylene chain, or a saltthereof.
 40. A compound as claimed in claim 39, wherein the compound isof the formula


41. A compound as claimed in claim 39, wherein A₂ is O.
 42. A compoundas claimed in claim 41, wherein R_(7′) and R_(7″) each independentlyrepresents a (1-4C)alkyl group or together with the nitrogen to whichthey are attached represent a pyrrolidine group that may bear one or twomethyl substituents, and each of R₈, R₉, R₁₀ and R₁₁ is independentlyselected from hydrogen, (1-4C)alkyl and phenyl, or the group

forms a divalent residue of (N-methylpyrrolidin-2-yl)diphenylmethanol,1-pyrrolidin-1-ylindan-2-ol,3-benzyloxy-2-N,N-dimethylamino-1-phenylpropan-2-ol, quinine, quinidine,hydroquinine, cinchonidine, cinchonine, hydrocinchonidine or ethylhydrocupreine.
 43. A method of preparing a sulfinylamine or sulfoxidestereoisomer, which comprises reacting a compound as claimed in claim 39with a first organometallic reagent of formula R¹M to afford a compoundof formula

and then either reacting this compound with a second organometallicreagent of formula R²M to afford a sulfoxide stereoisomer of formulaR¹—SO—R² in which R¹ and R² each independently represents an organicgroup, or with an alkali metal amide to afford a sulfinylaminestereoisomer.
 44. A method as claimed in claim 43, in which the firstorganometallic reagent is an organomagnesium halide.
 45. A method asclaimed in claim 44, in which the first organomagnesium halide is analkyl or arylmagnesium halide.